The invention relates to a substrate provided with a blood-compatible surface and to a method of forming same. More particularly, the blood-compatible surface is produced by coupling to at least part of the surface a physiologically active substance having an inhibitory effect on the formation of blood clots or having the capability of breaking down blood clots formed. The coupling includes a polyacid that is covalently bonded to the surface, the physiologically active substance being bonded to the polyacid.
As is known, various attempts have been made to improve the blood compatibility of various kinds of biomaterials by immobilizing on their surface heparin or heparin analogues. Thus it is known from U.S. Pat. No. 4,526,714 to render the surface of a substrate biocompatible by coating it with a conjugate of heparin, heparinous material or heparin analogues and a protein, the conjugate being formed by coupling that is carried out in the presence of 1-ethyl-3-dimethylaminopropyl carbodiimide (EDC) and the like as a coupling agent. The conjugate is attached to the substrate surface at the sites of the surface where free functional groups suitable for binding to the conjugate are present. In order to effect the coupling needed to form this known conjugate, these free functional groups on the substrate surface are provided as free amino groups.
For the blood compatibility of this prior art substrate surface to increase, the degree of coverage of the surface with the conjugate must be increased, which, for all practical purposes, means that the substrate surface should have a similarly large number of free functional groups available which are suitable for binding. Since the surface of a substrate often does not have free functional groups such as amino groups, these groups should first be liberated from the substrate material. This can be effected, for example, by chemical means, which is then accompanied by an attack on, i.e. damage to, the substrate surface. This damage is, of course, more severe as the number of free functional groups that must be provided is increased.
It is a general object of the invention to provide a substrate having a blood-compatible surface, as well as to a process for making the same.
Another object of the invention is to provide a blood-compatible surface in which a large and typically controllable amount of a physiologically active substance is connected via anchoring sites available on the surface of a substrate.
Another object of the present invention is to provide a blood-compatible surface on at least a selected portion of a medical device while avoiding or causing disproportionately little damage to the substrate surface.
These and other objects, features and advantages of this invention will be clearly understood through a consideration of the following detailed description.
In summary, the invention is a substrate having a physiologically active substance covalently bonded to at least a portion of its surface via a polyacid, as well as to a method of making same. The polyacid, which according to the present invention means a polymer containing many free carboxylic acid groups, is covalently bonded to the surface of the substrate, and the physiologically active substance is attached to various of the free carboxylic acid groups of the polyacid.
The invention is based on the insight that, owing to the introduction of a polyacid in the link chain of the physiologically active substance to the substrate surface, the carboxyl groups of each polyacid molecule provide a large number of free functional groups not belonging to the original substrate surface, which can serve as many bonding sites for anchoring the physiologically active substance. Accordingly, although only a small number of functional groups, such as amino groups, are introduced to, or liberated on, the original substrate surface, the number of potential bonding sites for the ultimate substance affecting the coagulation of blood is increased dramatic-ally by the numerous multiple free carboxylic acid functional groups provided by the polyacid.